DE2124907A1 - 3 Amino 1,2,4 oxadiazoles, process for their preparation and medicinal preparations - Google Patents

Description

to the
Patent application

of the applicant:

CCase 55 253 - s)

ER SQUIBB & SONS, INC.,
New York, NY, V.St.A.

"3-Amino-l, 2,4-oxadiazoles, process for their preparation and Medicinal products' "

Priority: July 15, 1970, V.St.Α., No. 55 253

The invention relates to unsubstituted and substituted 3-amino-1,2,4-oxadiazoles and their salts with acids of the general type Formula I.

N ^C ~ ^mi 2

(D

in which R _{1 is} a hydrogen or halogen atom, an alkyl or alkoxy radical, R _{2 is} a hydrogen atom, an alkyl or G ^ _g -cycloalkyl rust, a phenyl, alkylphenyl, alkoxyphenyl, halophenyl or trifluoromethylphenyl group and R ^, a hydrogen atom or an alkyl radical, a phenyl, alkylphenyl, alkoxyphenyl or halophenyl group and where all alkyl and alkoxy radicals are unbranched or branched and 1 to 7 carbon

109884/1871

contain carbon atoms.

Specific examples of alkyl radicals (or the

• Alkyl residues in the alkylphenyl groups) are the methyl, ethyl, Propyl, isopropyl or butyl group. Specific examples of alkoxy radicals (or the alkoxy radicals in the alkoxyphenyl groups) are the methoxy, ethoxy, propoxy and isopropoxy groups. Specific examples of cycloalkyl radicals are the cyclopropyl, Cyelobutyl, cyclopentyl and cyclohexyl groups. Fluorine, chlorine, bromine and iodine atoms come into consideration as halogen atoms, but chlorine and bromine atoms are preferred.

Alkyl and alkoxy radicals with 1 to 3 carbon atoms are preferred. Preferred cycloalkyl create contain 5 or 6 carbon atoms.

R ^ preferably denotes a hydrogen atom or an alkoxy group, preferably the methoxy group. IL, i ^s "k is preferably a hydrogen atom, an alkyl radical with 1 to 3 carbon atoms, t a cycloalkyl radical with 5 or 6 carbon atoms, a phenyl or p-alkoxyphenyl group, in particular the p-methoxyphenyl group. &, Preferably means a hydrogen atom.

The compounds of general formula I are obtained by cyclization an N- (hydroxyamidino) -2-phenylacetamide or its Salt with an acid such as a hydrohalic acid such as the hydrochloride, the general formula II

109884/1871

NOH

CO-NH-C-NH.

(H)

in which R-, -Rp and R ^ have the above meaning, in the presence of a base, for example an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, in an aqueous medium, preferably at low temperatures, for example at about 0 to 5 C,
manufactured. For the preparation of the acid addition salts can
inorganic or organic acids can be used.

The compounds of the general formula II can be selected from the corresponding Phenylacetic acid halides, preferably the chlorides, of the general formula III

CO-hal

(III)

in which R ₁ , R ₂ and R, have the above meaning and hai is a halogen atom, produced by reaction with cyanamide at low temperatures, for example below 5 ° C., in an alkaline solution
will.

The Phenylessignäurehalogenic-.e of the general formula III are from the corresponding. '! Phenylacetic acid and thionyl chloride manufactured.

109884/1871

. . - 4 - The resulting phenylaetylcyanamide of the general formula IV

CO-NH-CN

(IV)

is with hydroxylamine or its salt, e.g. a Hydrohaloge-.nid like the hydrochloride, in the presence of a hydrogen halide acceptor, such as pyridine or another base, converted to the compound of general formula II.

The compounds of the invention are valuable medicaments with anti-inflammatory properties. For example, you can reduce local inflammations, such as those that occur in edema, be used. This was demonstrated in the rat paw test, with the subplantar garrageenin in a rat hind paw indicated and a local edema is generated.

Thus, the * invention also relates to medicinal preparations that are marked * are due to a content of a compound of the general formula I as a medicinal substance.

The examples illustrate the invention.

example 1

5-Amino-5-benzyl-1,2,4-oxadiazole

56 g (0.8 mol) of hydroxylamine hydrochloride are dissolved in 250 ml of pyridine dissolved and gradually mixed with 85 g (0.5-3 mol) phenylacetylcyanamide with stirring (prepared under the conditions the Schütten-Baumann reaction from pienylacetyl chloride

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Cyanamide). The reaction mixture is cooled so that the! Temperature not exceeding 40 ⁰ C increases. The reaction mixture is then left. Stand for 20 hours, dilute with water and add 30% sodium hydroxide solution until the reaction is clearly alkaline. The mixture is stirred until the first crystals separate out, then cooled to 0 to 5 ° C. and left to stand for a few hours at this temperature. obtained 56.6 g of 3-AminQ-5-benzyl-l, 2,4-oxadiazole, mp 110 to 113 ⁰ C.

Example 2

3-Amino-5- (1-phenylpropyl) -l »2,4-oxadiazole 258 g of 2-phenylbutyryl chloride are dissolved in 500 ml of acetone and simultaneously with sodium hydroxide solution at a temperature of 0 to 5 ^° C. to give a mixture of 60 g Cyanamide, 136 ml of 30 percent sodium hydroxide solution and 1.35 liters of water were added. The P _H value is constantly monitored and should not fall below 10 to 11. The mixture is stirred for 1 hour and the clear solution is then acidified with concentrated hydrochloric acid to a strongly acidic reaction, the temperature being kept below 5 ^° C.

The separated oil is taken up in chloroform and separated from the water. The chloroform solution is dried with magnesium sulfate and the solvent is distilled off. There remain 269 g of crude 2-phenylbutyroylcyanamide, which is dissolved in 860 ml of ethanol without further purification. This solution is added to a solution of 151 g of hydroxylamine hydrochloride in 345 ml of pyridine. The reaction is exothermic. External cooling ensures that the temperature does not exceed 40 ^° C

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increases,

The reaction mixture is left to stand for 16 to 18 hours, the solution is then evaporated and 2 η sodium hydroxide solution is added to it until it has a strongly alkaline reaction. To give 3-amino-5- (l-phenylpropyl) -l, 2,4-oxadiazole as a precipitate · After recrystallization of the product from etv / a 300 ml of ethanol is obtained 138 g of the compound from E. 99 to 100 ⁰ C. ,

The compounds of general formula I listed in the table below are prepared by the process according to Example 2, phenylacetyl chlorides having the stated substituents E ₁ , R _{2 being} used instead of 2-phenylbutyryl chloride.

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α ι ««

21249Ö7

C-JSH,

I Il Il

_c - » c ν

"^ he

R-

Example r

R ₃ P.,

Outlined from

H 156-158 methanol

H -CH ₂ CH ₂ CH ₃ H 89-91 n-heptane

-CH (CH ₃ ) ₂ H 107-109 n-heptane

H 108-112 isopropanol

91-93 £ etr? Läthe ^: r

8 'CH ₅ O

H 133-136 isopropanol

9 CH ₃ O

(/ \ VOCH- H 149-1-51 methanol

10 'CH ₃ O

H 134-135 isopropanol

11

H

fi ^ 248-252 methylene glycol OFSOINM. INSPECTED

Claims (14)

Claims 3-Amino-l, 2,4-oxadiazoles and their salts with acids of general Formula I. (D in which R _{1 is} a hydrogen or halogen atom, an alkyl or alkoxy radical, R _{2 is} a hydrogen atom, an alkyl or C * £ cycloalkyl radical, a phenyl, alkylphenyl, alkoxyphenyl, halophenyl or trifluoromethylphenyl group and R is a hydrogen atom, an alkyl radical, a phenyl, alkylphenyl, alkoxyphenyl or halophenyl group and all alkyl and alkoxy radicals are straight or branched and contain 1 to 7 carbon atoms. 2. A compound according to claim 1 of the general formula I, in which Rj and R, are each hydrogen atoms and R _{2 is} an alkyl radical. 3. A compound according to claim 1 of the general formula Ϊ, in which R _{1 is} a hydrogen atom and R ₂ and R are each alkyl radicals. 4. A compound according to claim 1 of the general formula I, in which R ₁ and R ^ are each hydrogen atoms and Rp is a cycloalkyl radical. 109884/1871 5. A compound according to claim 1 of general formula I, in which R _{1 is} an alkyloxy radical, R _{2 is} a phenyl or alkoxyphenyl group and R ^ is a hydrogen atom. 6. A compound according to claim 1 of the general formula I, in which R ₁ , R ₂ and R ^ are each hydrogen atoms. 7. A compound according to claim 2 of the general formula I, in which the alkyl radical is an ethyl group · 8. A compound according to claim 2 of the general formula I, in which the alkyl radical is an eropyl group. 9. A compound according to claim 4 of the general formula I in which the Cycloalkylreat is a Cyelopentylgruppe. 10. A compound according to claim 4 of general formula I in which the cycloalkyl radical is a cyelohexyl group. 11. A compound according to claim 5 of the general formula I, in which the alkoxy radicals are each methoxy groups. 12. Process for the preparation of the compound of the general Formula I according to claim 1, characterized in that a compound of the general formula II NOH CO NH or their salt with an acid in which R ₁ , R ₂ and R- are in Claim 1 have given meaning, with a base in aqueous 109884/1871 - ίο - according to the medium to react and, if appropriate, the compound obtained is converted into a salt by reaction with an acid. 13. The method according to claim 12, characterized in that an alkali metal hydroxide is used as the base. 14. Medicinal preparation containing a 3-amino-1,2,4-oxadiazole
according to claim 1 or its pharmacologically acceptable salt as a medicinal substance. 109884/1871